Cannabinoids and the Brain

Abstract

The cannabinoid system in the brain is targetted in the use and abuse of preparations from the Cannabis plant. This system is composed of synthetic enzymes for the endogenous lipid‐derived ligands, the cannabinoid receptors they
activate and the enzymes which transform them. These endocannabinoids are amides, such as anandamide, or esters, such as 2‐arachidonoylglycerol,
whose primary target in the central nervous system is the CB1 cannabinoid receptor, a G protein‐coupled receptor expressed to unusually high levels. Δ9‐Tetrahydrocannabinol (THC) appears to be the sole psychoactive entity present in Cannabis plant, which elicits the characteristic responses in man and animals. The pharmacology and biochemistry of the endocannabinoid
system has been thoroughly investigated since the identification of CB1 cannabinoid receptors. As yet, however, the translation of this knowledge into a clinical setting has been of limited success.

Key Concepts:

Δ9‐Tetrahydrocannabinol appears to be the major psychoactive agent present in the Cannabis plant.

Δ9‐Tetrahydrocannabinol acts as a partial agonist at the CB1 cannabinoid receptor.

CB1 cannabinoid receptors appear to be the most densely expressed G protein‐coupled receptors in the brain.

Chemical structures of some cannabinoid ligands. Illustrated is the archetypal plant‐derived cannabinoid THC (Δ9‐tetrahydrocannabinol) and the structurally related synthetic agonist HU210. Note the increased chain length of the dimethylheptyl
sidechain. The dimethylheptyl sidechain is also present in CP55940, also a synthetic agonist, whereas one of the rings is
opened up. A third chemical class of cannabinoid agonists is represented by WIN55212‐2. Two endogenous agonists, based on
arachidonic acid derivatives, anandamide (AEA) and 2‐arachidonoylglycerol (2AG) are also represented. The central structure
is rimonabant, a CB1 cannabinoid receptor‐selective antagonist.

Figure 2.

Short‐term plasticity mediated by endocannabinoids. Illustrated is a synapse at which the amino acid glutamate acts as an
excitatory transmitter, although for clarity, a number of components have been omitted. (a) Depolarisation of the prejunctional
(upper) neurone leads to release of glutamate, which (at sufficient concentrations) activates α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic
acid (AMPA) glutamate receptors in the postsynaptic specialisation leading to postjunctional neuronal depolarisation. (b) Upon high‐frequency
stimulation, there is increased glutamate release, which ‘spills over’ to activate NMDA glutamate receptors and mGlu1/5 metabotropic glutamate receptors. The calcium influx via the NMDA receptor and the increased phosphoinositide turnover via
mGlu1/5 receptors combine to produce 2‐arachidonoylglycerol. (c) The 2‐arachidonoylglycerol diffuses in an anterograde manner to
activate a prejunctional CB1 cannabinoid receptor, which is coupled to a G protein‐activated inwardly rectifying potassium channel (GIRK). Opening of the potassium channel leads to hyperpolarisation of the prejunctional neurone, thereby reducing the subsequent
release of glutamate for a short period. Recovery is mediated by dissociation of 2‐arachidonoylglycerol and subsequent metabolism.